Invariant natural killer T cells in hematopoietic stem cell transplantation: killer choice for natural suppression

Guan, Peng; Bassiri, Hamid; Patel, Nilay A.; Nichols, Kim E.; Das, Rupali

doi:10.1038/bmt.2015.335

Cited by 19 publications

(17 citation statements)

References 100 publications

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“…Roles have also been described for iNKT cells helping to suppress Th1 responses and drive tolerogenic responses to grafts. As an example, following hematopoietic stem cell transfer, the presence of iNKT cells is predictive for survival with a reduction in graft versus host disease (GvHD) in patients and preclinical models ( 8 , 9 , 19 – 21 ).…”

Section: Overview Of Inkt Cell Biologymentioning

confidence: 99%

“…Other risks include antigen selection issues (e.g., off-tumor on-target) and GvHD caused by TCR mispairing in rTCR-expressing cells and via allogeneic cell therapy ( 67 ). Interestingly, while GvHD is a common concern for both CAR-T and rTCR-T, iNKT cells have been shown in pre-clinical models to suppress, not cause GvHD and are associated with reduced GvHD in the clinic ( 19 – 21 , 68 , 69 ), making for a potentially safer therapeutic approach. In light of both the promises and drawbacks of CAR-T and rTCR-T cells, there is growing interest in utilizing iNKT cells as an ideal platform for CAR or rTCR therapies (CAR-iNKT or CAR-rTCR).…”

Section: Future Clinical Trials: Car-inkt and Rtcr-inktmentioning

confidence: 99%

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Novel Approaches to Exploiting Invariant NKT Cells in Cancer Immunotherapy

2018

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iNKT cells are a subset of innate-like T cells that utilize an invariant TCR alpha chain complexed with a limited repertoire of TCR beta chains to recognize specific lipid antigens presented by CD1d molecules. Because iNKT cells have an invariant TCR, they can be easily identified and targeted in both humans and mice via standard reagents, making this a population of T cells that has been well characterized. iNKT cells are some of the first cells to respond during an infection. By making different types of cytokines in response to different infection stimuli, iNKT cells help determine what kind of immune response then develops. It has been shown that iNKT cells are some of the first cells to respond during infection with a pathogen and the type of cytokines that iNKT cells make help determine the type of immune response that develops in various situations. Indeed, along with immunity to pathogens, pre-clinical mouse studies have clearly demonstrated that iNKT cells play a critical role in tumor immunosurveillance. They can mediate anti-tumor immunity by direct recognition of tumor cells that express CD1d, and/or via targeting CD1d found on cells within the tumor microenvironment. Multiple groups are now working on manipulating iNKT cells for clinical benefit within the context of cancer and have demonstrated that targeting iNKT cells can have a therapeutic benefit in patients. In this review, we briefly introduce iNKT cells, then discuss preclinical data on roles of iNKT cells and clinical trials that have targeted iNKT cells in cancer patients. We finally discuss how future trials could be modified to further increase the efficacy of iNKT cell therapies, in particular CAR-iNKT and rTCR-iNKT cells.

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Section: Overview Of Inkt Cell Biologymentioning

confidence: 99%

Section: Future Clinical Trials: Car-inkt and Rtcr-inktmentioning

confidence: 99%

Novel Approaches to Exploiting Invariant NKT Cells in Cancer Immunotherapy

2018

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“…23 Compared with Treg infusion, iNKT infusion required fewer cells (100 000 iNKT vs 500 000 Treg in the same model) to reach optimal effect. 3,24 In addition, iNKT cells have inherent antiviral and antitumor abilities 25 that are desirable for patients with cGVHD. iNKT cells are persistent in host, as they can be detected in spleen, liver, and lung at least 2 weeks after infusion (not shown).…”

Section: Therapeutic Inkt Cell Infusion Reversed Established Cgvhdmentioning

confidence: 99%

Invariant natural killer T cells ameliorate murine chronic GVHD by expanding donor regulatory T cells

Paz²,

Thangavelu³

et al. 2017

Blood

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• Low doses of donor iNKT infusion prevent and reverse murine cGVHD.• iNKT efficacy in treating established cGVHD is dependent on donor Treg expansion.Chronic graft-versus-host-disease (cGVHD) can cause multiorgan system disease, typically with autoimmune-like features, resulting in high mortality and morbidity caused by treatment limitations. Invariant natural killer T cells (iNKTs), a small population characterized by expression of a semi-invariant T-cell receptor, rapidly produce copious amounts of diverse cytokines on activation that exert potent immune regulatory function.Here, we show that iNKTs are significantly reduced in a cGVHD murine model that recapitulates several aspects of autoimmunity and organ fibrosis observed in patients with cGVHD. Low iNKT infused doses effectively prevented and, importantly, reversed established cGVHD, as did third-party iNKTs. iNKTs suppressed the autoimmune response by reducing the germinal center (GC) reaction, which was associated with an increase in total Tregs and follicular Tregs (Tfr) that control the GC reaction, along with pathogenic antibody production. Treg depletion during iNKT infusions completely abolished iNKT efficacy in treating cGVHD. iNKT cell interleukin 4 production and GC migration were critical to cGVHD reversal. In vivo stimulation of iNKT cells by a-galactosyl-ceramide was effective in both preventing and treating cGVHD. Together, this study demonstrates iNKT deficiency in cGVHD mice and highlights the key role of iNKTs in regulating cGVHD pathogenesis and as a potentially novel prophylactic and therapeutic option for patients with cGVHD. (Blood. 2017;129(23):3121-3125)

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“…The suppression of graft-versus-host-disease (GvHD), while maintaining graft-versus-tumor effect has been shown to be highly dependent on the engraftment of donor iNKT cells, as failure to reconstitute iNKT cells after transplantation strongly correlated with disease relapse ( 84 – 87 ). Studies into the mechanisms of GvHD suppression show that iNKT cells modulate the overall immune response through production of Th2 cytokines such as IL-4, which in turn dampen inflammatory donor T cells, and promote Treg proliferation against both acute and chronic GvHD ( 88 – 91 ). These studies therefore highlight an importance function of the Th2 arm of activated iNKT cells in the facilitation of engraftment of allogenic donor cells against recurrence of leukemia.…”

Section: Immunoregulatory and Direct Cytotoxic Activities Of Inkt Celmentioning

confidence: 99%

Invariant Natural Killer T Cells in Immune Regulation of Blood Cancers: Harnessing Their Potential in Immunotherapies

2017

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Invariant natural killer T (iNKT) cells are a unique innate T lymphocyte population that possess cytolytic properties and profound immunoregulatory activities. iNKT cells play an important role in the immune surveillance of blood cancers. They predominantly recognize glycolipid antigens presented on CD1d, but their activation and cytolytic activities are not confined to CD1d expressing cells. iNKT cell stimulation and subsequent production of immunomodulatory cytokines serve to enhance the overall antitumor immune response. Crucially, the activation of iNKT cells in cancer often precedes the activation and priming of other immune effector cells, such as NK cells and T cells, thereby influencing the generation and outcome of the antitumor immune response. Blood cancers can evade or dampen iNKT cell responses by downregulating expression of recognition receptors or by actively suppressing or diverting iNKT cell functions. This review will discuss literature on iNKT cell activity and associated dysregulation in blood cancers as well as highlight some of the strategies designed to harness and enhance iNKT cell functions against blood cancers.

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Invariant natural killer T cells in hematopoietic stem cell transplantation: killer choice for natural suppression

Cited by 19 publications

References 100 publications

Novel Approaches to Exploiting Invariant NKT Cells in Cancer Immunotherapy

Novel Approaches to Exploiting Invariant NKT Cells in Cancer Immunotherapy

Invariant natural killer T cells ameliorate murine chronic GVHD by expanding donor regulatory T cells

Invariant Natural Killer T Cells in Immune Regulation of Blood Cancers: Harnessing Their Potential in Immunotherapies

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